The present invention relates to inhibitor compositions of phospholipase A(2) (hereinafter referred to as PLA (2)) activity characterized by comprising as the active ingredient either an oxa(thia)zolidine derivative or a pharmaceutically acceptable composite thereof, a use of said inhibitor compositions in mammalian which require to relieve sick conditions accompanied by the enhanced PLA(2) activity, and novel oxa(thia)zolidine derivatives which are useful as an active ingredient for said inhibitor compositions.
Inflammation is a series of defensive response process caused in the tissues, induced by the applied injurious events (inflammatory stimuli) on any parts of a human body. When the tissues are damaged by inflammatory stimuli that could be caused by bacterial infections, immunological responses or physical injuries, the tissues respond (acute inflammation) to the stimuli, followed by excluding the stimuli to repair the damages. Alternatively, if the exclusion is difficult, the damages are progressed to induce continuously tissue swelling (chronic inflammation). Inflammation is well known to be associated with several diseases, and various mediators are known to be associated with each step during the inflammation process, constituted with activation and interactions of various cells.
PLA(2) is a diverse class of enzymes, catalyzing preferentially the hydrolysis of the sn-2 acyl-ester of glycerophospholipids, that are major components of cell membranes, to liberate fatty acids. It is also well known that the PLA(2)s are responsible for deacylation-reacylation process required for cell membrane repair and maintenance, and the hydrolyzed products, as well as the further metabolites, are lipid mediators with strong diverse physiological activities. The liberated product, arachidonic acid with some activity as mediator, is further metabolized in respective inflammation-associated cells to prostagladins, thromboxanes, lipoxins, leukotrienes, etc., which induce characteristic physiological responses, respectively (Irvine, R., Biochemical Journal 204: 3-16 (1982).). The other product, lysophosphatidylcholine not only plays roles as mediator, but also is utilized as a precursor of platelet activating factor (hereinafter referred to as PAF). These lipid mediators play an essential role to maintain homeostasis of living organisms, however, when they produced to excessive amounts under sick conditions associated with inflammation, they could cause adversely effects. In fact, steroidal anti-inflammatory drugs and various non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAID) are known to interfere with the arachidonic acid cascade, have been widely used in clinical therapy. As PLA(2) is positioned at the upstream of the arachidonic acid cascade and is believed to be the rate-limiting step in the generation of these lipid mediators, this enzyme has been expected to be the promising target for research and development of novel anti-inflammatory drugs (Glaser, K. B., Advances in Pharmacology 32: 31-66 (1995).).
Recently, numerous PLA(2)s have been identified and rapidly become a large superfamily consisted of more than 15 isozymes are subdivided into four groups, on the basis of the protein structures and the characteristics in the enzymatic activities(Dennis, E. A., Trends in Biochemical Science, 22: 1-2 (1997), and Balsinde, J. et al, Annual Review of Pharmacology and Toxicology, 39: 175-189 (1999), etc.). Among them, it is noted that only the particular isozymes are shown high specificity against arachidonyl-phospholipids, as well as the enzymatic activity of the particular isozymes are selectively enhanced in a case of inflammatory disorder. As the examples for such inflammation-associated PLA(2)s, type IV-cytosolic PLA(2) (hereinafter referred to as IV-cPLA(2); molecular weight 85 kDa) and the subtypes IIA, IID, V and X of secretory PLA(2) (hereinafter referred to as sPLA(2); molecular weight 14 kDa) may be exemplified. Among these, IV-cPLA(2) is particularly considered as the responsible isozyme for producing the lipid mediators in the inflammatory diseases, which is supported by findings from the xe2x80x98knockoutxe2x80x99 (IV-cPLA(2)xe2x88x92/xe2x88x92)mice (Uozumi, N. et al, Nature 390: 619-622 (1997), and Bonventre, J. V. et al, Nature 390: 622-625 (1997).). Therefore, the enhanced lipid mediators production under sick conditions could be suppressed by inhibiting IV-cPLA(2) activity, thereby facilitating remedy and/or prevention of the inflammatory diseases. Such diseases can be exemplified as following: anaphylaxis induced by various inflammatory stimuli, septic shock, fever and pain; respiratory diseases, such as bronchitis, pneumonia, and adult respiratory distress syndrome; digestive diseases, such as inflammatory intestine disorder, Crohn""s disease, ulcerative colitis, hepatitis, and nephritis; cardiovascular diseases, such as vasculitis and arteriosclerosis; allergic inflammatory diseases, such as rhinitis, asthma and atopic syndromes; and auto-immune diseases such as rheumatism; ischemia/reperfusion injuries, such as cerebral infarction and myocardial infarction; nerve degenerative diseases, solar keratosis, psoriasis, and the like.
However, as no drug has been developed yet, which shows remedial effects in the clinical therapies by inhibiting the enzyme activity, it is desired to develop such a new drug that can specifically and comprehensively control the lipid mediators production in inflammatory diseases, with excellent therapeutic and preventive effects.
In WO97/05135, compounds represented by the following general formula; 
are disclosed as oxa(thia)zolidine derivatives having activity of inhibiting the PLA (2) activity. However, the compounds which show to have said inhibitory activity are limited to ones wherein the second and the fourth positions are substituted by either oxo or thio. Furthermore, in WO93/10789, 2-imino-4-oxothiazolidine derivative represented by the following chemical formula is disclosed. 
It is described in Jpn. Pat. Appln. KOKAI publication No. 63-41471 that the oxa(thia)zolidine derivatives related to the present invention have acaricidal activity. However, it is not known so far that those oxa(thia)zolidine derivatives have PLA(2) inhibitory activity or anti-inflammatory activity.
As described above, it is understood that the enhanced PLA(2) activity plays a major role in the progress of various inflammatory diseases. Therefore, an object of the present invention is to provide medicinal compositions which is effective to remedy the inflammatory sick condition and to cure or prevent the relevant disease, and novel compounds to be used for the medicinal composition.
As a result of the studies by the inventors of the present invention for aiming at achieving the aforementioned object, it is found out that the oxa(thia)zolidine derivatives, which had been known to have acaricidal activity, have been found out also having inhibitory activity on PLA(2), thereby reaching the present invention.
The present invention is constituted with the following aspects (1) through (12).
(1) A medicinal composition characterized by containing as the active ingredient either a compound represented by a general formula (1) or a pharmaceutically acceptable composite thereof; 
wherein X represents oxygen or sulfur,
R1 represents hydrogen, C1-4 alkyl or C1-4 haloalkyl,
R2 represents phenyl optionally substituted by A1, naphthyl optionally substituted by A1, 5 to 6-membered heterocyclic group optionally substituted by A1 containing at least one heteroatom selected from a group consisting of oxygen, sulfur and nitrogen, quinolyl optionally substituted by A1, or a group represented by a formula (2); 
wherein Q represents xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94OCH2Oxe2x80x94,
R3 represents hydrogen, C1-4 alkyl optionally substituted by A2, C1-4 alkoxy optionally substituted by A2, C1-4 alkylcarbonyl optionally substituted by A2, C1-4 alkoxycarbonyl optionally substituted by A2, C2-4 alkenylcarbonyl optionally substituted by A2, phenyliminomethyl optionally substituted by A3, phenyl optionally substituted by A3, anilino optionally substituted by A3, or a group represented by the following formulae; 
wherein Y represents oxygen or sulfur, R4 represents hydrogen or C1-4 alkyl, R5 represents C1-6 alkyl optionally substituted by A2, C2-6 alkenyl optionally substituted by A2, C2-6 alkynyl optionally substituted by A2, C1-6 alkoxy optionally substituted by A2, C2-6 alkenyloxy optionally substituted by A2, mono- or di-(C1-6 alkyl)amino optionally substituted by A2, C3-7 cycloalkyl optionally substituted by A4, C5-7 cycloalkenyl optionally substituted by A4, phenyl optionally substituted by A3, benzoyl optionally substituted by A3, anilino optionally substituted by A3, C1-6 alkoxycarbonyl optionally substituted by A2, phenylsulfonyl optionally substituted by A3, C1-6 alkoxysulfonyl optionally substituted by A2, mono- or di-(C1-6 alkyl)aminosulfonyl optionally substituted by A2, or 5- to 7-membered heterocyclic group optionally substituted by A4 containing at least one atom selected from a group consisting of oxygen, sulfur and nitrogen as a heteroatom, and n represents 0, 1 or 2,
R represents oxygen, sulfur or a group represented by a formula of Nxe2x80x94G, wherein G represents hydrogen, nitro, cyano, C1-4 alkyl optionally substituted by A2, C1-4 alkoxy, C1-4 alkylcarbonyl, phenyl optionally substituted by A3, benzoyl optionally substituted by A3, anilino optionally substituted by A3, a group represented by a formula of NHCOR6, wherein R6 represents C1-4 alkyl or phenyl optionally substituted by A3, or a group represented by the following formula; 
wherein Z represents oxygen or sulfur, R7 represents C1-4 alkyl, C3-7 cycloalkyl optionally substituted by A4, phenyl optionally substituted by A3, benzoyl optionally substituted by A3, or optionally substituted 5- to 6-membered saturated heterocyclic group,
A1 represents halogeno, amino, nitro, cyano, C1-12 alkyl, C2-6 alkenyl, C1-4 haloalkyl, C3-7 cycloalkyl, phenyl optionally substituted by halogeno, C1-4 alkyl or C1-4 haloalkyl, pyridyl, thienyl, C1-4 alkoxy, methylenedioxy, C1-4 alkylthio, C1-4 alkylsulfenyl, C1-4 alkylsulfonyl, mono- or di-(C1-4 alkyl)amino, C1-4 haloalkoxy, benzyl, phenethyl, phenoxy, phenylthio, C1-4 alkoxycarbonyl, C1-4 haloalkoxycarbonyl, C1-4 alkylcarbonyloxy, carbamoyl, or mono- or di-(C1-4 alkyl)carbamoyl,
A2 represents halogeno, C1-4 alkoxy, C1-4 alkoxy C1-4 alkoxy, amino, mono- or di-(C1-4 alkyl)amino, C1-4 alkylcarbonyloxy, C1-4 alkoxycarbonyl, halo C1-4 alkoxycarbonyl, C1-4 alkylcarbamoyl, di-(C1-4 alkyl)carbonylamino, morpholino, phenyl, or pyridyl optionally substituted by halogeno,
A3 represents halogeno, hydroxy, oxo, mercapto, nitro, amino, cyano, C1-4 alkyl, C1-4 haloalkyl, pyridyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfenyl, C1-4 alkylsulfonyl, mono- or di-(C1-4 alkyl)amino, C1-4 haloalkoxy, C1-4 alkylcarbonyl, C1-4 alkoxycarbonyl, C1-4 haloalkoxycarbonyl, carbamoyl, mono- or di-(C1-4 alkyl)carbamoyl, or C1-4 alkoxycarbonyl C1-4 alkylthio, and
A4 represents halogeno, hydroxy, oxo, C1-4 alkyl, halo C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, halo C1-4 alkoxy, halo C1-4 alkylthio, C1-4 alkoxy C1-4 alkoxy, C1-4 alkylsulfonyl, C1-4 alkoxycarbonyl, or C1-4 haloalkoxycarbonyl,
provided that R is oxygen or sulfur, R3 represents a group represented by the following formula; 
wherein Y, R4 and R5 are as defined above.
(2) Compounds represented by a general formula (1xe2x80x941); 
wherein X, R1, R2 and R3 are as defined in the section (1) described above, G1 represents nitro, cyano, C1-4 alkylcarbonyl, benzoyl optionally substituted by A3, NHCOR6, wherein R6 represents C1-4 alkyl or phenyl optionally substituted by A3, or a group represented by the following formula; 
wherein Z and R7 are as defined in the section (1) described above, and A3 is as defined in the section (1) described above.
(3) An inhibitor of PLA(2) activity comprising as the active ingredient at least one selected from a group consisting of heterocyclic compounds represented by the general formula (1) and the pharmaceutically acceptable composites thereof.
(4) A use of a composition for a mammalian animals which requiring remedy for inflammatory diseases or disorders, where the composition is characterized by containing as the active ingredient at least one selected from a group consisting of heterocyclic compounds represented by the general formula (1) and the pharmaceutically acceptable composites thereof.
(5) A method to remedy or reduce inflammatory diseases or disorders, curing and/or preventing taking turn for the worth by administering a medicinal composition, which is comprising an effective dose of at least one selected from a group consisting of compounds represented by the general formula (1) and the pharmaceutically acceptable composites thereof to a mammalian requiring treatment.
(6) The method defined in the section (5) described above; wherein the inflammatory diseases or the disorders are any of anaphylaxis, allergic inflammation, asthma, rhinitis, bronchitis, pneumonia, and adult respiratory distress syndrome, inflammatory intestine disorder, Crohn""s disease, ulcerative colitis, ischemia/reperfusion injuries, vasculitis, arteriosclerosis, hepatitis, nephritis, nerve degenerative diseases, arthritis, dermatitis, solar keratosis, psoriasis, septic shock and fever.
(7) The method defined in the section (5) described above, wherein the progress of the sick condition is due to inflammatory disease or disorder that is accompanied with the enhanced PLA(2) activity.
(8) The method defined in the section (5) described above, wherein the inflammatory disease or disorder is mediated by pro-inflammatory lipid mediators, such as arachidonic acid and the metabolites thereof, and/or lysophosphatidylcholines, and/or PAF.
(9) The method defined in the section (8) described above, wherein the pro-inflammatory lipid mediators are suppressed by the inhibitor of PLA(2) activity.
(10) A use of a heterocyclic derivative of the general formula (1) for manufacturing of a medicinal composition, which is used for reducing inflammatory and/or allergic sick condition and/or sick condition associated with immunity, and/or for the remedy of such diseases and disorders.
(11) A use of a composition as a medicine, where the composition contains as the active ingredient at least one selected from a group consisting of heterocyclic derivatives represented by the general formula (1) and the pharmaceutically acceptable composites thereof.
(12) A use of a composition as an anti-inflammatory drug, anti-allergic drug and/or immune controlling drug, where the composition contains as the active ingredient at least one selected from a group consisting of heterocyclic derivatives represented by the general formula (1) and the pharmaceutically acceptable composites thereof.
In the compounds according to the present invention, which are represented by the general formula (1),
X represents oxygen or sulfur,
R1 represents hydrogen; C1-4 alkyl selected from methyl, ethyl, propyl, isopropyl, butyl, i-butyl, sec-butyl and t-butyl; or C1-4haloalkyl, such as chloromethyl, fluromethyl, bromomethyl, dichloromethyl, trichloromethyl and pentafluromethyl,
R2 represents phenyl optionally substituted by A1; naphthyl optionally substituted by A1; 5- to 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, sulfur and nitrogen, such as thienyl, furyl, tetrahydrothiapyranyl, 2H, 5H, 6-H-thiapyranyl, pyranyl, tetrahydropyranyl, pyridyl, pyrimdyl, imidazolyl, oxazolyl, and thiazolyl, optionally substituted by A1; quinolyl optionally substituted by A1; or a group represented by the following formula (2); 
wherein Q represents a group represented by xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94 or xe2x80x94OCH2Oxe2x80x94,
R3 represents hydrogen; C1-4 alkyl, such as methyl and ethyl, optionally substituted by A2; C1-4 alkoxy, such as methoxy, ethoxy and propoxy, optionally substituted by A2; C1-4 alkylcarbonyl, such as acetyl, ethylcarbonyl, propylcarbonyl and butylcarbonyl, optionally substituted by A2; C1-4 alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl, optionally substituted by A2; C2-4 alkenylcarbonyl, such as ethenylcarbonyl and allylcarbonyl, optionally substituted by A2; phenylimino-methyl optionally substituted by A3; phenyl optionally substituted by A3; anilino optionally substituted by A3; or a group represented by the following formulae; 
wherein Y represent oxygen or sulfur,
R4 represents hydrogen, or C1-4 alkyl such as methyl and ethyl,
R5 represents C1-6 alkyl, such as methyl and ethyl, optionally substituted by A2; C2-6 alkenyl, such as ethenyl and allyl, optionally substituted by A2; C2-6 alkynyl, such as ethynyl and propynyl, optionally substituted by A2; C1-6 alkoxy, such as methoxy, ethoxy and butoxy, optionally substituted by A2; C2-6 alkenyloxy, such as ethenyloxy and allyloxy, optionally substituted by A2; mono- or di-(C1-6 alkyl)amino, such as methylamino, dimethylamino and ethylamino, optionally substituted by A2; C3-7 cycloalkyl, such as cyclopropyl, cycloheptyl and cyclohexyl, optionally substituted by A4; C5-7 cycloalkenyl such as cyclohexenyl optionally substituted by A4; phenyl optionally substituted by A3; benzoyl optionally substituted by A3; anilino optionally substituted by A3; C1-6 alkoxycarbonyl, such as methoxycarbonyl and ethoxycarbonyl, optionally substituted by A2; phenylsulfonyl optionally substituted by A3; C1-6 alkoxysulfonyl such as methoxysulfonyl optionally substituted by A2; mono- or di-(C1-6 alkyl)aminosulfonyl, such as methylaminosulfonyl, dimethylaminosulfonyl and diethylaminosulfonyl, optionally substituted by A2; or 5- to 7-membered heterocyclic group containing at least one selected from oxygen, sulfur and nitrogen as an heteroatom, optionally substituted by A4, and n represents 0, 1 or 2, and
R represents oxygen, sulfur or a group represented by a formula of Nxe2x80x94G, wherein G represents hydrogen, nitro, cyano, C1-4 alkyl optionally substituted by A2, C1-4 alkoxy, C1-4 alkylcarbonyl, phenyl optionally substituted by A3, benzoyl optionally substituted by A3, anilino optionally substituted by A3, NHCOR6, wherein R6 represents C1-4 alkyl or phenyl optionally substituted by A3, or a group represented by the following formula; 
wherein Z represents oxygen or sulfur, R7 represents C1-4 alkyl, C3-7 cycloalkyl optionally substituted by A4, phenyl optionally substituted by A3, benzoyl optionally substituted by A3, or optionally substituted 5- to 7-membered heterocyclic group.
The 5- to 7-membered heterocyclic group in the definition for the group represented by R5 and R7 means a saturated or unsaturated heterocyclic group constituted by 5 to 7 atoms and containing at least one heteroatom selected from oxygen, sulfur and nitrogen. Particularly, the 5- to 7-membered heterocyclic group includes tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, pyrimidinyl, pyridyl, and the like, and examples for the substituted xe2x80x9c5- to 7-membered heterocyclic groupxe2x80x9d includes N-methylpiperidinyl, 2,6-dimethylmorpholino, 3-methyloxathianyl, 6-methoxytetrahydropyranyl, and the like.
In the definition for the groups represented by A1, A2, A3 and A4, the halogeno denotes fluoro, chloro, bromo, iodo and the like, the C1-4 alkyl denotes a normal or branched chain alkyl having 1 to 4 carbon atoms, which specifically includes methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, s-butyl and t-butyl,
the C1-12 alkyl denotes pentyl, hexyl, dodecyl and the like in addition to said C1-4 alkyls,
the C1-4 haloalkyl denotes chloromethyl, bromomethyl, trifluoromethyl and the like,
the C3-7 cycloalkyl means a cyclic saturated hydrocarbon containing 3 to 7 carbon atoms, which specifically includes cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like,
the C1-4 alkoxy denotes methoxy, ethoxy and the like, and the C1-4 alkylthio denotes methylthio, ethylthio and the like,
the C1-4 alkoxy C1-4 alkoxy denotes methoxymethy, ethoxymethyl, methoxyethyl and the like,
the alkylsulfenyl denotes methylsulfenyl, ethylsulfenyl and the like, and the C1-4 alkylsulfonyl denotes methanesulfonyl, ethanesulfonyl and the like,
the mono- or di-(C1-4 alkyl)amino denotes methylamino, dimethylamino, ethylamino, methylethylamino and the like,
the C1-4 haloalkoxy denotes chloromethoxy, bromomethoxy, trifluoromethoxy, chloroethoxy, fluoroethoxy and the like,
the C1-4 alkoxycarbonyl denotes methoxycarbonyl, ethoxycarbonyl and the like, the C1-4 haloalkoxycarbonyl denotes chloromethoxycarbonyl, trifluoromethoxycarbonyl and the like, and C1-4 alkylcarbonyloxy denotes acetoxy, ethylcarbonyloxy and the like, and
the mono- or di-(C1-4 alkyl)carbamoyl denotes methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl and the like,
provided that R is oxygen or sulfur, R3 represents a group represented by the following formula; 
wherein Y, R4 and R5 are as defined above.
Among the compounds according to the present invention, the compounds in which R is a group represented by Nxe2x80x94G1 are novel compounds which have not been described in the previous references. Furthermore, among the compounds in which R is either oxygen or sulfur, most compounds in which R2 is naphthyl optionally substituted by A1, 5- to 6-membered heterocyclic groups optionally substituted by A1, quinolyl optionally substituted by A1, or a group represented by the formula (2), are novel compounds.
xe2x80x9cThe pharmaceutically acceptable compositexe2x80x9d denotes a composite comprising the compound described above and an atoxic low-molecular compound those interact with ionic, hydrogen or coordinate bonds each other, at a particular combining ratio, and the compound should be liberated after the composite is solubilyzed in an aqueous solution. Specific examples for the pharmaceutically acceptable composite include salts with ionic materials such as hydrochlorides, organic acids, amino acids and the like, and solvates such as hydrates.
Now, the process for manufacturing the compounds according to the present invention is explained below.
Among the compounds represented by the general formula (1), the compounds except the novel compounds represented by the general formula (1xe2x80x941) and the pharmaceutically acceptable composite thereof may be prepared according to the preparation process disclosed in Jpn. Pat. Appln. KOKAI Publication No. 63-41471, etc.
The compounds represented by the general formula (1xe2x80x941) may be prepared according to the following process.
Preparation Process 1: The compounds wherein G1 is either cyano or nitro, and X is oxygen: 
wherein R1, R2, R5 and Z are as defined above, G1xe2x80x2 is either cyano or nitro, and R3xe2x80x2 represents the same groups represented by R3 except groups represented by a formula of Yxe2x80x2NR4R5 wherein Yxe2x80x2 represents Cxe2x95x90O or Cxe2x95x90S, and R4 and R5 are as defined above.
Preparation Process 2: The compounds wherein G1 is either cyano or nitro and X is sulfur may be prepared according to the process described in Jpn. Pat. Appln. KOKAI Publication No. 63-41471. 
Preparation process 3: The compounds wherein G1 and/or R3 is Yxe2x80x2NR4R5 may be prepared according to the following reaction formulae.

The reaction of the compound (2) and the compound (3) in the preparation process 1 may be carried out in an organic solvent for 1 to several hours at the temperature ranging from room temperature to the boiling point of the used solvent. As the organic solvent for the above reaction, alcohols, dioxane, THF, DMF and the like may be used.
The respective reactions of the compounds (1-2), (1-5), (1-10) and (1-12) with a halide are carried out in an organic solvent in the presence of a base for 1 to scores of hours at the temperature ranging from xe2x88x9220xc2x0 C. to the boiling point of the used solvent, and preferably from 0xc2x0 C. to 50xc2x0 C. As the organic solvent for these reactions, DMF, THF, DMSO, alcohols and the like may be used. As the base for these reactions, sodium hydride may be used, or any of alkoxides, triethylamine, 1,8-diazabicyclo(5,4,0)undecene-7 (hereinafter referred to as DBU) and the like may be used as well.
The respective reactions of the compounds (1-2), (1-5) and (1-8) with either a cyanate or an isothiocyanate represented by a formula of R5NCZ may be carried out in an organic solvent in the presence of a base for 1 to scores of hours at the temperature ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C., and preferably from 0xc2x0 C. to room temperature. As the organic solvent for these reactions, DMF, DMSO, THF, dioxane, benzene, ethyl acetate and the like may be used. As the base for these reactions, triethylamine, DBU, Pyridine and the like may be used.
After each reaction represented above, work-up may be employed as conventionally to obtain the objective compound.
The chemical structures of the compounds according to the present invention were determined by means of MASS, NMR, etc.
The chemical structures of the compounds according to the present invention were determined by means of MASS, NMR, etc.
The compounds represented by the general formula (1) respectively include their structural isomers associated with at least the fourth and fifth positions of the oxa(thia)zolidine portion and their optical isomers. In addition, when R3 in the compound is hydrogen, the following tautomers may be arisen. 
It is to be noted that each of the compounds according to the present invention is not limited to the specific isomers, namely compounds may include all possible isomers as well as possible racemic modifications. Furthermore, depending on circumstances, the compounds according to the present invention also may include the prodrugs and the metabolites of the compounds indicated above.
Now, the medicinal composition according to the present invention and the use thereof are explained below.
The compound represented by the general formula (1) or the pharmaceutically acceptable composite thereof may be administrated to humans and animals either directly or together with common carriers for pharmaceutical formulations. For applying the composite, the administration route is not limited, and either route of systemic administration or topical application, i.e. non-systemic administration, may be selected appropriately upon necessity. Examples of the drug form for medical treatment include pharmaceutical formulations for oral administration such as tablets, capsules, granules, and powders, drinkable solutions, troches and the like; and parenteral solutions or suspensions for intravenous injection, intramuscular injection, subcutaneous injection and the like. In addition, other administration routes, such as through rectum with suppositories, and through lung (through nose or inhalation through mouth) with aerosols, powder inhalants, etc. may be employed for applying the medicinal composition according to the present invention. As pharmaceutical formulations suitable for the topical application to penetrate the active ingredient into the inflammatory regions through skins and mucosae, solutions, liniments, creams, emulsions, ointments and pastes, as well as drops suitable for the treatment to eyes, ears and noses may be exemplified. There is no limit for the amount of the active ingredient to be applied, and therefore, the dose may be appropriately selected in a wide range depending upon the administration routes, the applied compounds, and the treated patients, namely to humans or animals. In order to exert the desired medicinal effectiveness, the compound of the present invention is preferably administrated at a daily dose of 0.01-100 mg per kg body weight, with or without dividing the dose into several times. For the pharmaceutical formulations, it is preferable to contain the active ingredient in unit dosage form at a dose of 0.01 to 1,000 mg.
The pharmaceutical formulations for oral administration comprising the compound according to the present invention, such as tablets, capsules, granules and drinkable solutions, may be prepared according to any of the conventional methods. More specifically, the tablets may be prepared by mixing the compound represented by the general formula (1) or the pharmaceutically acceptable composite thereof with pharmaceutical fillers, such as starch, lactose, gelatin, magnesium stearate, talc, gum arabic, and the like, and forming into tablets. The capsules may be prepared by mixing the compound represented by the general formula (1) or the pharmaceutically acceptable composite thereof with an inactive pharmaceutical filler or diluent, and then charged into capsules made of hard gelatin, soft capsules, or the like to. The medicated syrups and elixirs for oral administration may be prepared by mixing the compound represented by the general formula (1) or the pharmaceutically acceptable composite thereof with a sweetener such as sucrose, an antiseptic such as Methylparaben and Propylparaben, a coloring agent, a flavor, and the like. Further, the parenteral pharmaceutical formulations of the compound of the present invention may be prepared according to any of the conventional processes. For example, a parenteral pharmaceutical formulation may be prepared by dissolving the compound represented by the general formula (1) or the pharmaceutically acceptable composite thereof with a sterilized liquid carrier. As the liquid carrier, water or saline solution may be preferably used. In order to provide the solution with a desired transparency, stability and congeniality for the parenteral use, approximately 0.1 to 1,000 mg of the active ingredient may be dissolved in either water or an organic solvent, and further dissolved with polyethylene glycol having a molecular weight of 200 to 5,000. For the preparation of the solution, it is preferable that a lubricant, such as polyvinylpyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose, and methyl cellulose, is incorporated therein. Furthermore, a bactericide such as benzyl alcohol, phenol and Thimerosal, and a fungicide may be incorporated into the solution, in addition, an osmotic pressure conditioner, such as sucrose and sodium chloride, a local anesthetic, a stabilizer, a buffer agent and the like may be incorporated into the solution upon necessity. More stable pharmaceutical formulation for parenteral use may be provided by removing moisture in the frozen preparation following to the filling, by means of freeze-drying technique known in the field. Accordingly, it is also possible to resolve the lyophilized powder thereof to prepare a pharmaceutical formulation just before the use.
Now, the present invention is further explained with reference to the examples for the pharmaceutical formulations comprising the compound according to the present invention. However, it should be noted that the following examples are only for the purpose of illustrating the present invention, and that the present invention is not limited to the following examples.
A compound of the present invention, lactose, corn starch and crystalline cellulose were incorporated thoroughly. The mixture was formed into the granules with 5% aqueous solution of methyl cellulose, and the granules were passed through a sieve of 300 mesh and then dried carefully. The dried granules were incorporated with magnesium stearate and then prepared into tablets according to the conventional method to obtain 1,000 tablets.
(The Pharmacopoeia of Japan)
The compositions recited above were incorporated and crushed into fine particulates. The particulates of the mixture were then stirred thoroughly so as to obtain the homogenous mixture. The mixture was then charged into capsules made of gelatin for oral administration use to obtain 1,000 pieces of two-pieces type gelatin capsules.
The Parabens, sodium metabisulfite and sodium chloride were dissolved with approximately half of the final volume of distilled water for injection use at 80xc2x0 C. while stirring. Then, the obtained solution was cooled down to 40xc2x0 C. The compound of the present invention, and subsequently polyethylene glycol and polyoxyethylene sorbitan monooleate were added to the solution and dissolve therewith. Next, the rest portion of the distilled water was added into the solution so as to adjust the volume to the final volume mentioned. The solution was then filtered through an appropriate filter to sterilize to obtain the pharmaceutical formulation of aqueous solution suitable for parenteral use.
The compound of the present invention was incorporated into the base material so as to be homogeneous therein.
The compound of the present invention was incorporated into ethanol and then added with 1 part of Propelant 22 to obtain a mixture. The mixture was then cooled down to xe2x88x9230xc2x0 C. and then placed in a charging apparatus. Next, an amount of the mixture required for a administration was transferred into a stainless container and was diluted with the rest portion of the Propelant 22 to prepare the solution for aerosol. The stainless container was then mounted with a valve unit to be ready for the administration.
The compound of the present invention was mixed with lactose to obtain a homogeneous mixture. The mixture was then charged into an inhaler for dry powder.
The compound of the present invention was passed through No. 60 mesh U.S. sieve and then suspended in saturated fatty acid glyceride having been melted beforehand with minimum heat. The mixture was charged into a molding for suppositories with the indication capacity of 2 g and then cooled.
Although the compounds represented by the general formula (1) or the pharmaceutically acceptable composites thereof show to have strong inhibitory activity on the liberation of arachidonic acid during inflammatory reaction, they have very weak inhibitory activity on the enzymatic hydrolysis due to secretary type IB-PLA(2) of porcine pancreas (hereinafter referred to as IB-sPLA(2); molecular weight 14 kDa) when using a phospholipid, of which carbon in the oleic acid substituent at the second position being labeled with a radioactive isotope, as the substrate. From this reason, an advanced safety can be expected for the compounds represented by the general formula (1) and the pharmaceutically acceptable composites thereof.
Since a part of the compounds of the present invention also shows hypolipemic activity by the oral administration, the compounds may be useful as anti-arteriosclerosis drugs.
Furthermore, a part of the compounds of the present invention has herbicidal, insecticidal, acaricidal and/or fungicidal activities as well, and they can be used as pesticides. In particular, an excellent performance can be expected, as a drug provided by the compounds which additionally have inhibitory activity against fungi that causes infectious diseases to mammalian animals, such as pneumonia by an opportunistically fungus infection.
Among the compounds of the present invention, represented by the general formula (1), the compounds in which R3 is C(xe2x95x90Y)NHR5 are particularly excellent in the activity as the aforementioned drugs, and the compounds in which R5 is tetrahydrofuranyl or tetrahydropyranyl are specially useful as said drugs.
Now, the present invention is further explained in detail with reference to the examples described below. However, it should be noted that the following examples are only for the purpose of illustrating the present invention, and the present invention is not limited to the following examples.